Amplification of genomic regions is frequently observed in human tumors and is one mechanism leading to the upregulation of genes that may critically affect cellular behaviour and drive tumour progression. Therefore, identifying the genes involved in amplification events represents a useful approach to increasing understanding of tumorigenic processes and may provide clinically useful markers.
Rhabdomyosarcomas (RMS) are the most common soft tissue sarcomas of childhood and account for around 5% of all childhood cancers. There are two main histological subtypes of RMS namely, alveolar (ARMS) and embryonal (ERMS). Both subtypes consist of cells that resemble and have markers for developing skeletal muscle. The alveolar subtype is generally associated with a poorer prognosis than ERMS and often has a t(2;13) (q35;q14) or t(1;13) (p36;q14) translocation which fuses the PAX3 or PAX7 genes, respectively, to FOXO1A (1-3). In addition to these translocations a number of other aberrations have been defined including regions of genomic amplification (4-10). There are a small but significant group of ERMS which demonstrate a poor response to treatment; the genetics of this group is not well defined.
Our previous work on RMS showed amplification of the 13q31-q32 chromosomal region in around 20% of ARMS studied (4). In addition, samples from a number of other tumour types have been reported with amplification of the 13q31-32 region including other sarcomas (leiomyosarcomas (11), malignant fibrous histiocytomas (12), lymphomas (13), breast cancers (14), small cell lung carcinomas and various neurological tumours (15-17)). Also, the widely available leukaemic cell line K562 has been shown to have amplification of the 13q31-32 region in addition to the translocation associated with the BCR-ABL fusion gene (18). Recent work on a few lymphoma cell lines derived from different types of lymphoma defined a minimum region of amplification at 13q31-32 to an approximately 4 megabase region (13). This region contained the glypican 5 gene (GPC5) which was shown to be expressed and was suggested as a possible target for the amplification event in lymphomas. Whether this gene plays a functional role in lymphomas and whether the same gene is involved in other tumour types with genomic aberrations in this region remains to be determined.
In a previous analysis of RMS samples we used a new approach to profile global changes in differential expression which targets chromosomes called comparative expressed sequence hybridization (CESH) (19). The data from 45 cases was used in a study to examine the classification potential of these profiles (20). Here we compare chromosomal level genetic and expression data for the 13q31-32 region and suggest that amplification is not the only mechanism leading to increased expression of gene(s) from this region. In view of the frequent differential expression from the 13q31-32 region in addition to its amplification we have sought to implicate gene(s) from this region in the development of RMS. This could provide a target for therapeutic approaches to treat these, and potentially other tumours.